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PMID: 20972331 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques.

The Journal of clinical investigation ·Vol. 120 ·No. 11 ·2010-11-00 ·Pages 3878-90

Titanji K, Velu V, Chennareddi L, Vijay-Kumar M, Gewirtz AT, Freeman GJ, Amara RR

Abstract

Rapid progression to AIDS is a significant problem, especially in developing countries, where the majority of HIV-infected individuals reside. As rapid disease progression is also frequently observed in SIV-infected macaques, they represent a valuable tool to investigate the pathogenesis of this condition in humans. Here, we have shown that pathogenic SIV infection in rhesus macaques resulted in a rapid depletion (as early as week 2) of activated memory B (CD21-CD27+; mBAct) cells that was strongly associated with rapid disease progression. This depletion was progressive and sustained in rapid progressors, but less severe and transient in typical progressors. Because of the rapid and sustained depletion of mBAct cells, rapid progressors failed to develop SIV-specific Ab responses, showed a decline in non-SIV-specific Ab titers, and succumbed faster to intestinal bacterial infections. Depletion of mBAct cells was strongly associated with preferential depletion of mBAct cells expressing programmed death-1 (PD-1), and in vitro blockade of PD-1 improved their survival. Furthermore, in vivo PD-1 blockade in SIV-infected macaques enhanced Ab responses to non-SIV as well as SIV Ags. Our results identify depletion of mBAct cells as a very early predictor of rapid disease progression in pathogenic SIV infection and suggest an important role for the PD-1 pathway in depletion of mBAct cells and impaired humoral immune responses in SIV-infected macaques.

MeSH Terms
Animals Antibodies, Viral/blood,immunology Antigens, CD/immunology B-Lymphocytes/immunology Disease Progression Female Humans Immunologic Memory/immunology Lymphocyte Subsets/immunology Macaca mulatta/immunology,virology Male Simian Acquired Immunodeficiency Syndrome/immunology Simian Immunodeficiency Virus/immunology Viral Load
Chemicals
Antibodies, Viral Antigens, CD
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Titanji Kehmia
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Velu Vijayakumar
Chennareddi Lakshmi
Vijay-Kumar Matam
Gewirtz Andrew T
Freeman Gordon J
Amara Rama R
References (51)
51 references, click to expand
  1. Microbial translocation is a cause of systemic immune activation in chronic HIV infection.
    Nat Med. 2006 Dec;12(12):1365-71 PMID: 17115046
  2. B7, a B-cell-restricted antigen that identifies preactivated B cells.
    J Immunol. 1987 Nov 15;139(10):3260-7 PMID: 3500211
  3. Plasma viremia in macaques infected with simian immunodeficiency virus: plasma viral load early in infection predicts survival.
    J Virol. 1997 Jan;71(1):284-90 PMID: 8985348
  4. Role of flagellin in Crohn's disease: emblematic of the progress and enigmas in understanding inflammatory bowel disease.
    Inflamm Bowel Dis. 2009 May;15(5):789-95 PMID: 19107795
  5. Viral factors determine progression to AIDS in simian immunodeficiency virus-infected newborn rhesus macaques.
    J Virol. 1995 Jul;69(7):4198-205 PMID: 7769679
  6. Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection.
    Blood. 2006 Sep 1;108(5):1580-7 PMID: 16645169
  7. Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection.
    Blood. 2004 Mar 15;103(6):2180-6 PMID: 14604962
  8. Concurrent infections and HIV pathogenesis.
    AIDS. 2000 Sep 29;14(14):2071-81 PMID: 11061647
  9. Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily.
    J Exp Med. 2004 Oct 4;200(7):587-99 PMID: 15508184
  10. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses.
    Int Immunol. 1998 Oct;10(10):1563-72 PMID: 9796923
  11. B lymphocyte dysfunctions in HIV infection.
    Curr HIV Res. 2004 Jan;2(1):11-21 PMID: 15053337
  12. Determinants of disease in the simian immunodeficiency virus-infected rhesus macaque: characterizing animals with low antibody responses and rapid progression.
    J Gen Virol. 1998 Oct;79 ( Pt 10):2461-7 PMID: 9780052
  13. Loss of memory (CD27) B lymphocytes in HIV-1 infection.
    AIDS. 2001 May 25;15(8):957-64 PMID: 11399977
  14. Immunological memory: contribution of memory B cells expressing costimulatory molecules in the resting state.
    J Immunol. 2001 Nov 15;167(10):5669-77 PMID: 11698439
  15. Evidence of early B-cell dysregulation in simian immunodeficiency virus infection: rapid depletion of naïve and memory B-cell subsets with delayed reconstitution of the naïve B-cell population.
    J Virol. 2010 Mar;84(5):2466-76 PMID: 20032183
  16. Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area.
    J Immunol. 2009 Aug 1;183(3):2176-82 PMID: 19592645
  17. Early depletion of proliferating B cells of germinal center in rapidly progressive simian immunodeficiency virus infection.
    Virology. 2007 May 10;361(2):455-64 PMID: 17223151
  18. Discriminating gene expression profiles of memory B cell subpopulations.
    J Exp Med. 2008 Aug 4;205(8):1807-17 PMID: 18625746
  19. Detectable serum flagellin and lipopolysaccharide and upregulated anti-flagellin and lipopolysaccharide immunoglobulins in human short bowel syndrome.
    Am J Physiol Regul Integr Comp Physiol. 2008 Feb;294(2):R402-10 PMID: 18003793
  20. Natural history of HIV infection in the era of combination antiretroviral therapy.
    AIDS. 1999 Oct 1;13(14):1933-42 PMID: 10513653
  21. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study.
    Lancet. 2005 Jul 30-Aug 5;366(9483):378-84 PMID: 16054937
  22. Low pre-infection levels and loss of central memory CD4+ T cells may predict rapid progression in SIV-infected pigtail macaques.
    Virology. 2008 Nov 10;381(1):11-5 PMID: 18835006
  23. Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease.
    J Allergy Clin Immunol. 2008 Jul;122(1):12-9; quiz 20-1 PMID: 18547629
  24. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage.
    J Infect Dis. 1999 Apr;179(4):859-70 PMID: 10068581
  25. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection.
    J Exp Med. 2006 Oct 2;203(10):2281-92 PMID: 16954372
  26. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract.
    J Exp Med. 2004 Sep 20;200(6):749-59 PMID: 15365096
  27. PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status.
    AIDS. 2007 Oct 1;21(15):2005-13 PMID: 17885290
  28. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine.
    Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13866-71 PMID: 11698646
  29. Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.
    J Exp Med. 2007 Sep 3;204(9):2171-85 PMID: 17724130
  30. B7-H1 up-regulation impairs myeloid DC and correlates with disease progression in chronic HIV-1 infection.
    Eur J Immunol. 2008 Nov;38(11):3226-36 PMID: 18924219
  31. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
    Nature. 2006 Sep 21;443(7109):350-4 PMID: 16921384
  32. Differential association of programmed death-1 and CD57 with ex vivo survival of CD8+ T cells in HIV infection.
    J Immunol. 2009 Jul 15;183(2):1120-32 PMID: 19564339
  33. Host factors and the pathogenesis of HIV-induced disease.
    Nature. 1996 Dec 12;384(6609):529-34 PMID: 8955267
  34. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.
    Nat Med. 2006 Oct;12(10):1198-202 PMID: 16917489
  35. Enhancing SIV-specific immunity in vivo by PD-1 blockade.
    Nature. 2009 Mar 12;458(7235):206-10 PMID: 19078956
  36. Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells.
    Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13451-6 PMID: 19666505
  37. Rapid disease progression in human immunodeficiency virus type 1-infected seroconverters in India.
    AIDS Res Hum Retroviruses. 2002 Nov 1;18(16):1175-9 PMID: 12487823
  38. Tissue-specific B-cell dysfunction and generalized memory B-cell loss during acute SIV infection.
    PLoS One. 2009 Jun 19;4(6):e5966 PMID: 19543531
  39. SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection.
    Blood. 2007 Aug 1;110(3):928-36 PMID: 17440051
  40. Attenuated disease in SIV-infected macaques treated with a monoclonal antibody against FasL.
    Clin Dev Immunol. 2007;2007:93462 PMID: 18317535
  41. Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system.
    J Immunol Methods. 2004 Mar;286(1-2):111-22 PMID: 15087226
  42. Primary HIV-1 infection sets the stage for important B lymphocyte dysfunctions.
    AIDS. 2005 Nov 18;19(17):1947-55 PMID: 16260900
  43. Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination.
    J Virol. 2007 Jun;81(11):5819-28 PMID: 17376899
  44. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals.
    J Exp Med. 2008 Aug 4;205(8):1797-805 PMID: 18625747
  45. GM-CSF DNA: an adjuvant for higher avidity IgG, rectal IgA, and increased protection against the acute phase of a SHIV-89.6P challenge by a DNA/MVA immunodeficiency virus vaccine.
    Virology. 2007 Dec 5;369(1):153-67 PMID: 17698160
  46. Progression to symptomatic disease in people infected with HIV-1 in rural Uganda: prospective cohort study.
    BMJ. 2002 Jan 26;324(7331):193-6 PMID: 11809639
  47. B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression.
    Blood. 2003 Apr 1;101(7):2514-20 PMID: 12468426
  48. The role of motility as a virulence factor in bacteria.
    Int J Med Microbiol. 2002 Mar;291(8):605-14 PMID: 12008914
  49. Critical role for Env as well as Gag-Pol in control of a simian-human immunodeficiency virus 89.6P challenge by a DNA prime/recombinant modified vaccinia virus Ankara vaccine.
    J Virol. 2002 Jun;76(12):6138-46 PMID: 12021347
  50. A new memory CD27-IgG+ B cell population in peripheral blood expressing VH genes with low frequency of somatic mutation.
    J Immunol. 2006 Sep 15;177(6):3728-36 PMID: 16951333
  51. Persistent immune activation in HIV-1 infection is associated with progression to AIDS.
    AIDS. 2003 Sep 5;17(13):1881-8 PMID: 12960820
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI43271
Published
2010-11-00
Epub
2010-00-25
Pages
3878-90
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2964982
Subset
IM
Grants
NCRR NIH HHS · P51 RR00165 · United States
NIAID NIH HHS · P30 AI050409 · United States
NIAID NIH HHS · R01 AI057029 · United States
NIAID NIH HHS · R01 AI074471 · United States
NCRR NIH HHS · P51 RR000165 · United States
NIAID NIH HHS · R43 AI074471 · United States
NIAID NIH HHS · P01 AI08080192 · United States
NIAID NIH HHS · R01 AI074417 · United States
NIAID NIH HHS · R01 AI071852 · United States
Corrections
CommentIn
PMID: 20972328
External Links
PubMed source DOI: 10.1172/JCI43271 PMC Full Text View journal details
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